1. Field of the Invention
The present invention relates generally to systems and methods for the transdermal administration of drugs and more particularly to the use of porous, non-collapsible polymeric particles for containing the drugs and/or percutaneous drug enhancers within a matrix layer of a transdermal drug delivery device.
Transdermal delivery is a preferred route of drug administration under a variety of circumstances. Transdermal delivery is accomplished by exposing a source of the drug to a patient's skin for an extended period of time. Typically, the drug is incorporated in a matrix or reservoir from which it is released onto the patient's skin. The rate of release can be controlled by a membrane placed between the reservoir and the skin, by diffusion from a monolithic device, or by the skin itself serving as a rate-controlling barrier in the delivery system. Transdermal delivery enjoys a number of advantages including optimization of systemic concentration, enhanced therapeutic efficacy, reduced frequency of dosage, reduced side effects, and hepatic bypass which can increase the effective activity of the drug.
Numerous factors must be considered when designing systems for transdermal drug delivery. Of particular interest to the present invention, the rate of drug delivery to the skin and rate of penetration of the drug through the skin must be carefully controlled in order to optimize a particular drug therapy. The rate at which the drug is delivered from the device to the skin is most advantageously controlled by the use of rate-limiting membranes which are placed between the drug reservoir and the skin. Assuming that the skin is sufficiently permeable to the drug (i.e., absorption through the skin is greater than the rate of passage through the membrane), the membrane will serve to control the dosage rate experienced by the patient. In the case of relatively non-permeable drugs, however, the situation is somewhat more complex. Where a desired drug cannot be transported across the skin at a sufficiently high rate to achieve a therapeutically useful blood concentration, various ionophoretic and chemical approaches have been proposed to enhance drug permeability. Of particular interest to the present invention, chemical permeability enhancers can be administered simultaneously with the drug in order to increase the transport of drug through the stratum corneum.
Most commonly, the chemical permeability enhancer will be combined with the drug in the reservoir or matrix layer of transdermal delivery device. The enhancer is then released under similar kinetics as the drug so that the concentrations of the drug and the enhancer at the skin interface cannot be independently controlled other than by varying their respective initial concentrations. The inability to separately control the release rates of drug and enhancer renders the design of transdermal delivery systems much more difficult. For example, it may be necessary to provide excess drug and/or enhancer in order to achieve the concentration necessary to effect a desired release rate.
In order to improve control over the rate of drug delivery from a transdermal device and through a patient's skin, it would be desirable to provide devices which decouple the release rate of the drug from the release rate of the chemical permeability enhancer. In particular, it would be desirable to provide such transdermal delivery devices which allow both the amount and the release rate of both the drug and the chemical enhancer to be independently controlled within the device. In this way, the use of excess drug and/or enhancer will not be required and efficient drug utilization can be maximized.
2. Description of the Background Art
U.S. Pat. No. 4,687,481, describes a transdermal drug delivery system including a backing sheet and a macroporous face membrane having a reservoir therebetween. The reservoir contains an occlusive liquid base material having a plurality of drug-containing particles dispersed therein. The particles are in the form of drug-polymer solids or polymer-coated drug particles. U.S. Pat. No. 4,692,462, discloses the use of charged ion exchange resins for containing drugs within a transdermal delivery system. Salt concentration within a gel layer including the resin is varied to control the drug release rate. U.S. Pat. Nos. 3,797,494 and 3,731,683, disclose transdermal patches where drugs are incorporated in microcapsules dispersed in an adhesive layer. The drug release rate is controlled by diffusion from the microcapsules. U.S. Pat. No. 3,854,480, discloses a drug delivery reservoir device where solid drug particles are dispersed in a solid reservoir layer within a rate controlling membrane. German patent application DE 3333444A1 describes a transdermal patch having a gelatin matrix layer where the active substance is applied to a particulate carrier. Japanese patent application 59-84812 discloses a controlled release device having a drug-containing powder dispersed in a resinous sheet. EPO 226 240 discloses a topically applied emulsion having a bioactive agent-containing particulates dispersed therein. EPO 241 178 discloses antibiotics in polymeric particulates dispersed in a wafer-soluble polymer for application to the gums. The following U.S. Pat. Nos. are also of interest: 4,764,382; 4,747,845; 3,993,073; 3,948,254; 3,948,262; and 3,598,122.